title: Combination of cisplatin and radiation in cell culture: effect of duration of exposure to drug and timing of irradiation.
abstract: Responses to the combination of cisplatin (CDDP) and radiation in experimental and clinical studies have been reported to vary from high radiosensitization to clear sub-additivity. We examined the combined effect of CDDP with ionizing radiation in both murine mammary adenocarcinoma (EMT-6) and human ovarian carcinoma (OV-1063) cells with special reference to the duration of CDDP exposure and timing of irradiation. Cell survival was measured with a colorimetric assay of cell density. The nature of interaction of cisplatin and radiation was evaluated using isobolograms and a combination index (CI). Exposure of both cell lines to CDDP for 24 hr before irradiation yielded an additive or slightly sub-additive response only if the exposure was extended for a few more hours after irradiation. In EMT-6 cells, the combination of radiation with subsequent continuous as well as short-term (4 to 6 hr) CDDP treatment was found to have a clear sub-additive effect; dose escalation of each modality reduced the additional effect of the other. The sub-additive effect may be explained by a radiation-induced arrest of cells in late S phase, which was dose- and time-dependent. Post-radiation exposure to CDDP further increased the S-phase arrest. In contrast, a 2 hr post-radiation drug exposure resulted in a supra-additive combined effect. Our results stress the crucial role of the timing and the doses of both modalities as well as the duration of post-radiation drug exposure on their combined effect.
authors.affiliation: Sharett Institute of Oncology, Hadassah University Hospital, Jerusalem, Israel. Rafi@Hadassah.org.il
authors.forename: R
authors.initials: R
authors.lastname: Gorodetsky
authors.forename: F
authors.initials: F
authors.lastname: Levy-Agababa
authors.forename: X
authors.initials: X
authors.lastname: Mou
authors.forename: A M
authors.initials: AM
authors.lastname: Vexler
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000528:radiation effects*
chemical_list: D011838:Radiation-Sensitizing Agents; D002945:Cisplatin